Highlights Diabetes Research

Mouse embryo in the gastrula stage.
Mouse embryo in the gastrula stage. The outer endoderm consists of embryonic cells (red) and a few isolated extraembryonic cells (green). Strikingly, the accumulation of extraembryonic cells is on the posterior side, where they overlay the primitive strip. These posterior visceral endoderm cells play an important role in the patterning of the embryo.

Lowering Blood Glucose Levels More Effectively

Studies in cooperation with Sanofi Aventis have shown the mechanism of action of the combination therapy of metformin and SGLT2 inhibitors. SGLT2 inhibitors promote the excretion of sugar in the urine, thereby reducing blood glucose. This leads to an increased glucose production in the liver. Metformin, by contrast, lowers endogenous glucose production. Through the interplay of both substances, the decrease in blood glucose is effective and long lasting.

Susanne Neschen et al.: Metformin Supports the Antidiabetic Effect of a Sodium Glucose Cotransporter 2 Inhibitor by Suppressing Endogenous Glucose Production in Diabetic Mice. Diabetes 64 (2015) | doi: 10.2337/db14-0393

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Differentiation Mechanisms of Endoderm Progenitor Cells Identified

The Wnt/β-catenin signaling pathway and microRNA 335 are significantly involved in the formation of differentiated endoderm progenitor cells from stem cells. These organize themselves in germ layers and are thus the origin of different types of tissue, including the pancreas and its insulin-producing beta cells. The Wnt/β-catenin signaling pathway and microRNA 335 thus represent key molecular functions of stem cell differentiation, which could be used for beta cell replacement therapy in diabetes (www.hum-en.eu).

Silvia Engert et al.: Wnt/β-catenin Signalling Regulates Sox17 Expression and is Essential for Organizer and Endoderm Formation in the Mouse. Development (2013) | doi:10.1242/dev.088765

|| Dapeng Yang et al.: miR-335 Promotes Mesendodermal Lineage Segregation and Shapes a Transcription Factor Gradient in the Endoderm. Development (2014) | doi:10.1242/dev.104232

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Metformin Lowers Cholesterol

Metformin affects the blood lipid levels via activation of the AMPK protein complex in the liver. The researchers hypothesize that the genes FADS1 and 2 are thus downregulated, which is reflected in lower concentrations of three lipid metabolites, leading to lower LDL cholesterol levels. This is the result of a study of metabolite concentrations and the genetic information from blood samples of more than 1,800 participants of the large-scale KORA study.

Tao Xu et al.: Effects of Metformin on Metabolite Profiles and LDL Cholesterol in Type 2 Diabetes Patients. Diabetes Care 38 (2015) | doi: 10.2337/dc15-0658

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High-Fat Diet Increases Insulin Resistance

In the mouse model, a high-fat diet reduces the expression of enzymes of the epoxyeicosatrienoic acid synthesis pathway and thus indirectly inhibits insulin action. The epoxyeicosatrienoic acid synthesis pathway is a pharmacological target. Drugs that enhance it are currently being tested in clinical studies for cardiovascular indications.

Alexander Schäfer et al.: The Epoxyeicosatrienoic Acid Pathway Enhances Hepatic Insulin Signaling and is Repressed in Insulin-Resistant Mouse Liver. MCP 14 (2015) | doi: 10.1074/mcp.M115.049064

Adipose Network

How diet, the environment, genetics and the composition of intestinal bacteria flora interact in the development of the metabolic syndrome, is shown in a study in cooperation with the Joslin Diabetes Center in Boston. The study provides evidence for the evaluability and transferability of in vivo experiments between laboratories and has an impact on current research projects that aim to tackle obesity through the transfer of intestinal bacteria.

Siegfried Ussar et al:. Interactions between Gut Microbiota, Host Genetics and Diet Modulate the Predisposition to Obesity and Metabolic Syndrome. Cell Metabolism 22 (2015) | doi: 10.1016/j.cmet.2015.07.007

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Nanotunnels Improve Cellular Respiration

The protein calcineurin plays a central role in the adaptive regulation of body weight and energy homeostasis. For the first time, a mechanism has been described in flies and mice in which the cellular respiration is amplified by the formation of elongated mitochondrial nanotunnels, thus causing a general improvement of the energy and glucose metabolism throughout the entire body.

Paul Pfluger et al.:  Calcineurin Links Mitochondrial Elongation with Energy Metabolism. Cell Metabolism 22 (2015) | doi: 10.1016/j.cmet.2015.08.022

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Hormone Triplet Regulates Blood Glucose

A new substance that unifies the action profiles of three gastrointestinal hormones, lowers blood glucose levels in the animal model, reduces body fat to an unprecedented extent and improves fatty liver, cholesterol levels and calorie burning. The triple hormone acts specifically and equally at three target sites, the receptors of GLP-1, GIP and glucagon. GLP-1 and GIP induce increased insulin secretion and thus lower blood glucose levels. In addition, GLP-1 curbs the appetite. The third hormone – glucagon – increases calorie burning over the long term.

Brian Finan et al.: A Rationally Designed Monomeric Peptide Triagonist Corrects Obesity and Diabetes in Rodents. Nature Medicine 21 (2014) | doi: 10.1038/nm.3761

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Molecular Marker of Type 1 Diabetes

Prior to a diagnosis of type 1 diabetes, autoantibodies against the insulin-producing pancreatic cells circulate in the blood. In children, just before the first appearance of autoantibodies, researchers have observed a transient significant increase in the expression of genes associated with an antiviral interferon (IFN) immune response. The IFN immune response is often associated with a recent respiratory illness – a new indication that diseases of the upper respiratory tract also can contribute to the development of type 1 diabetes.

Ricardo C. Ferreira et al.: A Type I Interferon Transcriptional Signature Precedes Autoimmunity in Children Genetically at-risk of Type 1 Diabetes. Diabetes (2014) | doi: 10.2337/db13-1777

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Diagnostic Marker for Type 1 Diabetes in Adults

Based on the affinity of the antibody response against the enzyme glutamic acid decarboxylase (GAD), patients with LADA – a form of autoimmune type 1 diabetes in adulthood – can be distinguished from non-autoimmune type 2 diabetes patients. Patients with high GAD antibody affinity display low insulin production and need insulin therapy after a relatively short time.

Stephanie Krause et al.: GAD Autoantibody Affinity in Adult Patients with Latent Autoimmune Diabetes, the Study Participants of a GAD65 Vaccination Trial. Diabetes Care (2014) | doi: 10.2337/dc13-1719

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Preventive Insulin Vaccine Appears Promising

Evaluations of the international Pre-POINT Study indicate a positive immune response in at-risk children who were administered oral insulin. In the double-blind study, children with a high risk for type 1 diabetes were treated with oral insulin once a day for six months. The control group only received a placebo. The insulin was administered prophylactically as a vaccine at a time at which the children did not yet have any autoimmune response – that is, they had not yet developed any autoantibodies. The aim of this insulin vaccination is to develop immune tolerance to the body's own proteins and thus to prevent an autoimmune response which can lead to type 1 diabetes. In subsequent studies, the plan is to treat a larger number of participants with a high risk of developing type 1 diabetes. If the vaccine prevents the autoimmune disease permanently, a nationwide preventive vaccination would be possible.

Ezio Bonifacio et al.: Effects of High-Dose Oral Insulin on Immune Responses in Children at High Risk for Type 1 Diabetes  - The Pre-POINT Randomized Clinical Trial. JAMA. 2015;313(15):1541-1549. doi:10.1001/jama.2015.2928

Warning Signs of Diabetes

Based on a scoring system, data on non-specific physical symptoms were collected from approximately 10,000 participants of the population-based MONICA/KORA cohort study. Per score value, the risk of developing type 2 diabetes rose by two percent. This increase in risk was independent of classic diabetes risk factors, such as obesity, high blood pressure or smoking. The authors suggest considering appropriate symptom patterns as possible warning signs in the early detection of metabolic diseases.

Jens Baumert et al.: A Pattern of Unspecific Somatic Symptoms as Long-term Premonitory Signs of Type 2 Diabetes: Findings from the Population-based MONICA/KORA Cohort Study, 1984-2009. BMC Endocrine Disorders 14 (2014) | doi:10.1186/1472-6823-14-87

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Coordinated Cilia Movements

Cilia on epithelial tissues provide for the transduction of stimuli or the transport of secretions, for example in the lung or in the intestines. Cilia are anchored by basal bodies to the plasma membrane and localized at a specific position in a cell. This orientation takes place in the context of planar cell polarity development. Using the example of the inner ear, the authors show that the proteins Flattop and Dlg3 play an important role in the acquisition of planar cell polarity. Both proteins interact physically together in the inner ear and direct the correct positioning of the hair cells in the cochlea.

Moritz Gegg et al.: Flattop Regulates Basal Body Docking and Positioning in Mono- and Multiciliated Cells. E-Life 2014 | doi: 10.7554/eLife.03842

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Cilia and Insulin Secretion

Cilia are hair-like extensions on cells with important functions. It has now been shown that insulin receptors are situated on the cilia of beta cells of the pancreas. If the insulin-producing beta cells are stimulated, the insulin receptors on the cilia are overexpressed. Cilia thus play an important role in the secretion and signal transduction of the glucose-lowering hormone insulin. In the animal model significantly elevated blood glucose levels were found when the cilia were genetically reduced or functionally limited. Insulin secretion was also reduced in the preclinical model with defective cilia.

Jantje Gerdes et al.: Ciliary Dysfunction Impairs Insulin Secretion and Promotes Development of Type 2 Diabetes in Rodents.  Nature Communications 5 (2014) | doi: 10.1038/ncomms6308

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Risk Test for Diabetes after Pregnancy

Using a new method, an accurate prognosis of the probability of developing postpartum diabetes can be determined on the basis of simple parameters. Based on the data of 257 cases of gestational diabetes observed over a period of 20 years, an easy-to-use scoring system has been developed which can serve as a predictive model in the clinical setting.

Meike Koehler et al.: Development of a Simple Tool to Predict the Risk of Postpartum Diabetes in Women with Gestational Diabetes Mellitus. Acta Diabetologica (2015) | doi: 10.1007/s00592-015-0814-0

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Error in DNA Regulation Increases Risk of Diabetes

DNA markers often indicate an increased risk for certain diseases, but it is often not clear which DNA variant triggers a disease. Now a variant has been identified that is involved in type 2 diabetes. It is localized in a non-coding DNA region and interferes with the binding of transcription factors to the DNA. This leads to increased concentration of free fatty acids, a risk factor for a precursor stage of type 2 diabetes. The analysis of the DNA was achieved using a new method that compares the DNA-binding sites of different animal species with each other: The greater the similarity of the sequence, the greater their biological significance. Thus, important binding sites and their variants can be identified.

Melina Claussnitzer et al.: Leveraging Cross-Species Transcription Factor Binding Site Patterns: From Diabetes Risk Loci to Disease Mechanisms. Cell 156 (2014) 343–358 | doi:10.1016/j.cell.2013.10.058

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Insulin Activates Hypothalamic Region of the Brain

For the first time it has been demonstrated in humans that selective insulin action in specific brain regions improves glucose metabolism throughout the body. The effect could only be found in thin people, whereas overweight study participants were resistant to the insulin action in the brain. The studies show that altered reactions in the brain are involved in the development of whole-body insulin resistance, a central factor in type 2 diabetes.

Martin Heni et al.: Central Insulin Administration Improves Whole-body Insulin Sensitivity via Hypothalamus and Parasympathetic Outputs in Men. Diabetes 63 (2014) | doi: 10.2337/db14-0477

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Weight Gain and Intestinal Metabolism

Weight gain has consequences for metabolic performance and for the bacterial community in the gastrointestinal tract. Using methods of ultra-high resolution mass spectrometry on mice, metabolic profiles and the diversity of the intestinal flora were detected. In a second study it was shown that the metabolism in a diabetic animal model is characterized in particular by previously unknown sulfur-containing metabolites.

Alesia Walker et al.: Distinct Signatures of Host–microbial Meta-metabolome and Gut Microbiome in Two Q1 C57BL/6 Strains under High-fat Diet. The ISME Journal 8 (2014) | doi: 10.1038/ismej.2014.79 || Alesia Walker et al.: The Importance of Sulfur-containing Metabolites in Discriminating Fecal Extracts between Normal and Type 2 Diabetic Mice. Journal of Proteome Research 13 (2014) | doi: 10.1021/pr500046b

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Diabetes Patients with Good Self-Management Live Longer

Scientists have examined 340 KORA study participants with type 2 diabetes and surveyed them as to their patient behavior, including whether they regularly monitor their blood glucose levels, follow a diet plan and are physically active. Patients with good self-management have a significantly reduced mortality risk. This underscores the importance of the patient's behavior in the treatment of diabetes.

Michael Laxy et al.: The Association Between Patient-Reported Self-Management Behavior, Intermediate Clinical Outcomes, and Mortality in Patients With Type 2 Diabetes: Results From the KORA-A Study. Diabetes Care (2014) | doi: 10.2337/dc13-2533

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Vitamin D Deficiency Already Exists in Type 1 Prediabetes

A vitamin D deficiency has been observed in children with newly-diagnosed type 1 diabetes and those who have not yet developed the disease but have multiple autoantibodies. These low vitamin D levels precede the onset of the disease and may already be a result of the immune response. Early diagnosis can prevent serious metabolic disorders and can be used to elucidate underlying mechanisms. Moreover, predicting if and when the onset of type 1 diabetes will occur is crucial for prevention measures. To better estimate the importance of environmental influences, the study of larger populations is essential. To this end, the model project "Diabetes 2015" shall be carried out: a Bavaria-wide screening for early diagnosis of type 1 diabetes. This shall be integrated into routine child check-ups and enable affected families to participate in prevention trials.

Jennifer Raab et al.: Prevalence of Vitamin D Deficiency in Pre-type 1 Diabetes and its Association with Disease Progression. Diabetologia 57 (2014) | doi: 10.1007/s00125-014-3181-4

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Diabetes and Obesity More Common in Socioeconomically Deprived Regions

Living in a socioeconomically deprived region is a risk factor for diabetes mellitus and obesity. This applies regardless of the individual social status of the inhabitants. This is the conclusion reached by scientists of Helmholtz Zentrum München and the Robert Koch Institute. In the collaborative project, the data of more than 33,000 individuals who had participated in the telephone health survey Current Health in Germany (GEDA) were evaluated.

Werner Maier et al.: Area Level Deprivation is an Independent Determinant of Prevalent Type 2 Diabetes and Obesity at the National Level in Germany. Results from the National Telephone Health Interview Surveys ‘German Health Update’ GEDA 2009 and 2010. PLOS ONE (2014) | doi: pone.0089661

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Multihormone Molecule Restores Leptin Action in Obesity

A novel biomolecule which acts equally on the receptors for glucagon and glucagon-like peptide 1(GLP-1), which are hormones of the gastrointestinal tract, lowers body weight and improves glucose metabolism by means of increased sensitivity to the hormone leptin. Leptin is produced in adipose tissue and plays a key role in the regulation of energy balance. In the mouse model the treatment works even when a high-fat, high-sugar diet is continued.

Christoffer Clemmensen et al.: GLP-1/Glucagon Co-agonism Restores Leptin Responsiveness in Obese Mice Chronically Maintained on an Obesogenic Diet. Diabetes 63 (2014) | doi: 10.2337/db13-1609

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